This invention relates to antiviral compounds, compositions and pharmaceutical formulations comprising effective amounts of these compounds and methods for treating or preventing infections caused by viruses in mammals.
The ability of viruses to invade cells and parasitize cellular biochemical mechanisms for viral replication restricts the potential means and methods that can be used to selectively inhibit such replication. Very few antiviral agents which are non-toxic for non-infected cells are known. Furthermore, most antiviral agents are of limited effectiveness.
Retroviruses are particularly elusive targets for antiviral agents precisely because these viruses differ radically in their mode of replication from the DNA-containing and other RNA-containing viruses. Retroviruses become integrated into the cellular genome and their replication is probably mediated by cellular enzymes. This severely restricts the possibilities of eliminating the virus from the host cell. Only a few compounds are known to possess relatively selective (i.e. relatively noncytotoxic) anti-retroviral activity. The nucleoside analog 3'-azido-3'-dideoxythymidine also commonly known as azidothymidine (hereinafter referred to as AZT) and other nucleoside analogs (such as the dideoxycytidine analog of cytosine) owe their relative selectivity for virally-infected cells to their ability to inhibit retroviral functions (i.e., the activity of reverse transcriptase enzyme) more efficiently than they inhibit host cell functions (i.e., the activity of DNA polymerase). The use of such nucleoside analogs is limited due to their narrow spectrum of activity and their toxic side-effects when administered systemically to a host organism over long periods of time. Furthermore, long-term use of these drugs increases the likelihood of development of resistant mutants.
A member of the retroviral family, the Human Immunodeficiency Virus (HIV), is currently being spread in epidemic proportions in the U.S. and around the world. HIV is now believed to be the causative agent of Acquired Immune Deficiency Syndrome (AIDS). Two different serotypes of the virus have been identified to date: HIV-1 and HIV-2. Current estimates are that approximately 1.5 million people have been infected with HIV at this time in the United States alone. It is believed that the vast majority of individuals infected with the virus eventually will develop AIDS and are likely to succumb to opportunistic infections and/or malignancies.
The drug currently used against HIV infection is AZT. However, because of the toxicity of AZT and because its effectiveness is also otherwise limited, alternative antiviral agents (or at least agents of relatively low toxicity that could be used in conjunction with AZT therapy) are needed. Moreover, because of its toxicity, AZT is inappropriate for use prophylactically and therefore less toxic alternatives suitable for prophylactic use are desired. In addition, AZT-resistant strains of HIV have been recently reported.
Copending U.S. patent application Ser. No. 082,700 of D. Lavie et al. filed Aug. 7, 1987, discloses the antiviral activity of two aromatic polycyclic dione compounds: hypericin (Hy) and pseudohypericin (Ps).
Copending U.S. patent application Ser. No. 084,008 of D. Lavie et al. filed Aug. 10, 1987 expands upon the disclosure of U.S. application Ser. No. 82,700, now U.S. Pat. No.4,898,891 focusing on the use of Hy and Ps as effective anti-retroviral agents.
Copending U.S. patent application Ser. No. 172,064 filed Mar. 23, 1988 of D. Meruelo et al. discloses anti-retroviral compositions comprising effective amounts of Hy and Ps in combination with nucleoside analogs such as AZT and methods for treating retroviral infections.
In addition, copending U.S. patent application of Daniel Meruelo and Gad Lavie Ser. No. 299,971, filed Jan. 19, 1989 entitled Blood Purification System discloses compositions and methods for inactivating viruses and retroviruses present in blood, other body fluids and, more generally biological fluids, and articles used in the practice of such methods. The compositions comprised hypericin, pseudo-hypericin, isomers, analogs, homologs, and derivatives of aromatic polycyclic diones and mixtures of these compounds, all of which are also used in the present invention.
The present invention is directed to use of a variety of compounds structurally related to hypericin as therapeutic (or prophylactic) antiviral and antiretroviral agents in vivo.
Therefore, it is an object of the present invention to provide novel therapeutic agents for the treatment (or prevention) of viral infections. (Henceforth, the terms "virus" and "viral" will include "retrovirus" and "retroviral" unless explicitly stated otherwise.)
Another object of the present invention is to provide methods for treating mammals suffering from (or potentially exposed to) infections caused by viruses, especially HIV.
A further object of the present invention is to provide pharmaceutical formulations for treating individuals suffering from (or potentially exposed to) viral infections.
These and other objects of the present invention will be apparent to those of ordinary skill in the art in light of the present description accompanying drawings and appended claims.